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Structure and interactions of the Clostridium difficile S-layer with bacteriocins.

艰难梭菌 S 层的结构和与细菌素的相互作用。

基本信息

批准号：
BB/P02002X/1
负责人：
Per Bullough
金额：
$ 73.81万
依托单位：
University of Sheffield
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FP02002X%2F1
关键词：
Structure interactions Clostridium difficile layer

项目摘要

Clostridium difficile is an important human pathogen, causing serious illness and even death. C. difficile infection (CDI) occurs most commonly in the hospital setting, affecting patients who are already suffering ill health, but infections in the community are an increasing problem. C. difficile is naturally resistant to many common antibiotics so whilst these antibiotics kill the beneficial bacteria in the human gut they have no effect on C. difficile; indeed they actually benefit the bacterium by removing competition. The proteins on the surface of the C. difficile bacterium are the appendages through which it interacts with its environment and the human host. The C. difficile surface is coated in a single layer of protein that forms a two-dimensional crystal that wraps around the bacterium. This surface layer (S-layer) acts as a coat of armour to protect the bacterium from attack by our immune system and is essential for the bacteria to cause disease. Despite the importance of the S-layer we know very little about how it assembles on the cell surface and what it looks like. We have recently collaborated with a biotech company who have developed new therapeutic particles that attach to the S-layer to kill the C. difficile. These particles, called Avidocins, consist of a needle inside a spring-loaded sheath. When the Avidocin binds to the cell surface the sheath contracts and drives the needle through the cell wall and membrane, killing the bacterium. Although we know that Avidocins bind to the S-layer we do not know exactly how they recognise the S-layer, where they bind, what changes they undergo while binding, how the contraction is triggered or how the needle penetrates the various layers of the cell envelope.In this project we will combine our complementary expertise in C. difficile biology and powerful electron microscopy to:1. Understand the structure and organisation of the S-layer. This is essential information if we want to develop new treatments that target the S-layer to treat or prevent CDI.2. Understand the structure of the Avidocin particle both on its own and in the act of binding to and killing a C. difficile cell.There is an urgent need to develop new therapies to combat CDI and, in particular, to develop therapies which kill C. difficile but do not cause damage to the beneficial gut bacteria. A new therapy would ideally target a distinctive part of the bacterium which is essential for its lifecycle. The S-layer is an ideal candidate for this sort of intervention because it doesn't resemble the surface of any other kind of bacteria. Avidocins are promising therapeutic agents in their own right and are also closely related to natural viruses that infect C. difficile (bacteriophage). There is a lot of interest in the potential of bacteriophage to treat infections. Many of the features of Avidocin killing that we will study are directly relevant to bacteriophage infection, including binding to the S-layer, contraction of the spring-loaded sheath and penetration of the cell envelope. Our work on S-layer will identify ways in which this important structure can be targeted to tackle CDI.

艰难梭菌是一种重要的人类病原体，可导致严重疾病甚至死亡。C.艰难梭菌感染（CDI）最常发生在医院环境中，影响已经患有疾病的患者，但社区中的感染是一个日益严重的问题。C.艰难梭菌对许多常见抗生素具有天然耐药性，因此虽然这些抗生素可以杀死人类肠道中的有益细菌，但对艰难梭菌没有影响。事实上，它们通过消除竞争而使细菌受益。C.艰难梭菌是其与环境和人类宿主相互作用的附属物。梭艰难梭菌的表面覆盖着一层蛋白质，形成一个二维的晶体，包裹着细菌。这个表面层（S层）作为一个盔甲的外套，以保护细菌免受我们的免疫系统的攻击，是必不可少的细菌引起疾病。尽管S层很重要，但我们对它如何在细胞表面组装以及它的外观知之甚少。我们最近与一家生物技术公司合作，该公司开发了新的治疗颗粒，可以附着在S层上杀死C层。很难这些被称为Avidocins的颗粒由弹簧鞘内的针组成。当Avidocin结合到细胞表面时，鞘收缩并驱动针穿过细胞壁和细胞膜，杀死细菌。虽然我们知道Avidocins与S层结合，但我们并不确切知道它们如何识别S层，它们在哪里结合，它们在结合时发生了什么变化，收缩如何被触发或针如何穿透细胞包膜的各个层。在这个项目中，我们将联合收割机结合我们在C.艰难的生物学和强大的电子显微镜：1。理解S层的结构和组织。如果我们想开发针对S层的新治疗方法来治疗或预防CDI，这是必不可少的信息。了解Avidocin颗粒本身的结构以及结合并杀死C的行为。迫切需要开发对抗CDI的新疗法，特别是开发杀死C.但不会对有益的肠道细菌造成损害。一种新的疗法将理想地针对细菌的一个独特部分，这是其生命周期所必需的。S层是这种干预的理想候选者，因为它不像任何其他种类细菌的表面。抗生物素蛋白本身是有前途的治疗剂，并且与感染C.艰难梭菌（噬菌体）。人们对噬菌体治疗感染的潜力很感兴趣。我们将研究的Avidocin杀伤的许多特征与噬菌体感染直接相关，包括与S层的结合、弹簧加载鞘的收缩和细胞包膜的穿透。我们在S层上的工作将确定如何将这一重要结构用于解决CDI。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structure and assembly of the S-layer in C. difficile.

DOI：
10.1038/s41467-022-28196-w
发表时间：
2022-02-25
期刊：
Nature communications
影响因子：
16.6
作者：
Lanzoni-Mangutchi P;Banerji O;Wilson J;Barwinska-Sendra A;Kirk JA;Vaz F;O'Beirne S;Baslé A;El Omari K;Wagner A;Fairweather NF;Douce GR;Bullough PA;Fagan RP;Salgado PS
通讯作者：
Salgado PS

Pathogenicity and virulence of Clostridioides difficile.